JPS6011421A - Antilipemic agent - Google Patents

Abstract

PURPOSE:To provide an antilipemic agent containing 24,25-dihydrocholecalciferol as an active component, and having antilipemic activity and high safety. CONSTITUTION:The objective antilipemic agent contains 24,25-dihydroxycholecalciferol (abbreviated as the present substance) of e.g. formula I . The present substance has been already known to have antihypercalcemic and antitumor activities, etc., however, it has been newly found that the compound also has antilipemic activity. It is useful as an active component of antilipemic agent, remedy for arteriosclerosis, and remedy for hydperlipemia. The active component is preferably 24R,25-(OH)2-D3 of formula II. In contrast with the activated vitamin D3 analog, the present substance has extremely high safety. Dose: preferably 0.5-1X10<4>mug/day.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a blood lipid-lowering agent containing 24,25-dihydroxycholecalciferol as an active ingredient.

As a result of intensive research into substances that are endogenous to healthy humans and have proven safety, the present inventors discovered that 24.25-dihydroxycholecalciferol (24.25-dihydroxycholecalciferol)
Hereinafter, this substance or 24.25-(Ol-4)2-D3
It has been discovered that the compound (abbreviated as ) has a number of physiologically active effects,
It already has anti-hypercalcemic effects, anti-ulcer effects, prevents immune function decline, regulates magnesium metabolism, anti-hypersemia, and regulates blood sugar.

It has been found to have antitumor effects. Subsequently, as a result of repeated research, it was discovered that the drug has a "lower blood lipid-lowering effect" and the present invention was achieved.

This substance is a highly safe substance as described below, and also has a blood lipid-lowering effect, making it useful as an active ingredient in blood lipid-lowering agents, arteriosclerosis treatments, and antihyperlipidemic agents. It is.

All of these substances are known substances and have the following structures, for example, as described by Anthony W, Norman, Vitamin
inD: MOLECUL, ARBIOLOGYAND
CLINICAL NUTRITION.

MARCEL DEKKER, ING, I), 1-92
(1980).

24' 25- (OH)2-D3 24R,25-(
OH)2-D30S24S, 25-(OHI2-D3This substance is 24
(<, 25- (OH) -D , 24S, 25-
3(OH)2-D3 or a mixture thereof, but 1x24R,25-(OH)2-D3'calco is particularly preferred. The blood lipid-lowering agent of the present invention contains the above-mentioned substances as active ingredients, and is used in various formulations as shown below. The blood lipid-lowering agent of the present invention can be administered orally, parenterally, or directly;
One additional dose is preferred.

Preparations containing this substance as an active ingredient are used in dosage forms such as tablets, powders, granules, suppositories, capsules, alcoholic solutions, oily solutions, and aqueous suspensions. As the oily solvent, mono-hemoglyceride esters of intermediate fatty acids, corn oil, cottonseed oil, peanut oil, fish liver oil, oily Nisdel, etc. are used. Also preferable are Chiri A oil, Glyrelin, and the like. Other ingredients include lactose, starch lυ, talc, magnesium stearate, sorbic acid, sorbic acid salt, sugar or its derivative alcohol, physiological saline, surfactant, R
Anti-inflammatory agents or other pharmaceutical agents may be used in conjunction with this substance.

The substance may be present in unit dosage form at 2 x 10 to 4 vA%.
, preferably 2 x 10 to 1% by weight.

In addition, this substance is administered in doses of 0.1 μg to 1×1 per day for adults.
05 μg, preferably 0.5 to 1×10 4 μg.

Next, we will describe the results of investigating the acute toxicity of this substance.

Acute toxicity: This substance was dissolved in ethanol using 10 1crt male mice (body weight 25±3(1)), and the ethanol concentration was 2.
%J, dissolved in 1-lyglyceride ester of intermediate fatty acid of sea urchin, and administered orally (p,o,). The dose is 1
00+n (1/ka). All 10 animals were observed for stone symptoms for 2 weeks after administration, but all survived without any abnormalities. After sacrifice, blood samples, biochemical tests, anatomical findings, and histopathological examinations were performed. , there was no difference in any way from the control group to which only triglyceride ester of intermediate fatty acid containing 2% ethanol was administered.

Therefore, since the LD value of this substance for oral administration is 100 mg0/k() or more, active vitamin D AnaL1
1α-(OH)-D (orally administered 1α-(OH)-D)
．． D is 1111 iJ/k (less than I), so the genuine product can be said to be extremely safe.

EXAMPLES The effects of the present invention will be specifically explained below with reference to Examples. In addition, this substance used in the examples (Y24R, 25
-(OH)-D, and the bM"1M photoisomer at position 24 was confirmed by Tetrahedron.
Letters No. 26.0.2203-22
0Ci, 1975.

Example 1 Blood lipid-lowering effect [Important male gray rabbits were orally given solid feed (CRl) containing 1% CORESDEL, and after about 3 months, the increase in serum lipid components was observed. This was confirmed and used as an experimental arteriosclerosis model animal. The present substance was dissolved in MO-(triglyceride ester of C8-C carboxylic acid) 0 and 100 μ!+/kill of the present substance was administered lightly to these arteriosclerosis model animals.

Blood was collected from the ear vein over time after administration, and serum lipid analysis was performed.Changes in total cholesterol in the white fluid were measured by an enzymatic method, and β-lipoprotein was measured by a turbidimetric method. The results are shown in Table 1 below. Note that administration of only MCT was used as a control.

In view of the above-mentioned toxicological and pharmacological properties of this substance, it is understood that this substance can be put to practical use as a blood lipid-lowering agent, an anti-arteriosclerosis agent, etc.

Table 1 Example 2 0.5 μg of 24R,25-(OH) -D3 was added to MCTlkg, which was irradiated with a 400 W high-pressure mercury lamp for 72 hours without bubbling argon to eliminate peroxide. Soft capsules were prepared by heating and dissolving the following shell components and using a soft capsule making machine in a conventional manner.

Shell formulation example Gelatin 10 parts Glycerin 2 parts M Preservative (edylparaben) 0.05i 1 part Titanium White 0.2 parts Water 0.2 parts by weight (as per final form) Capsules containing 1 μg, 2 μg, 5 μg, or 10 μg were prepared.

Claims (2)

[Claims] (1) A blood lipid-lowering agent containing 24.25-dihydroxycholecalciferol as an active ingredient. (2) 24.2! The blood lipid-lowering agent according to claim 1, wherein the i-dihydroxycholecalciferol is 24R,25-dihydroxycholecalciferol.